Abstract
Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.
Highlights
Microtubules (MTs), dynamic polymeric filaments composed of α-tubulin and β-tubulin heterodimers, are key components of the cytoskeleton of eukaryotic cells
Carba1 was not toxic for this cell line (Figure S3). These results indicate that Carba1 does not induce additional toxicity
We looked for the binding site of Carba1 on tubulin
Summary
Microtubules (MTs), dynamic polymeric filaments composed of α-tubulin and β-tubulin heterodimers, are key components of the cytoskeleton of eukaryotic cells. Their crucial roles in cell division and physiology mainly rely on their ability to rapidly polymerize or depolymerize. Targeted perturbation of this finely tuned process constitutes a major therapeutic strategy. A number of compounds bind to the tubulin-MT system. They can be roughly classified into MT-stabilizers such as taxanes or epothilones, and MT-destabilizers such as vinca alkaloids, combretastatin, and colchicine [1]. It has been demonstrated that binding of vinca alkaloids or colchicine prevents the curved-to-straight conformational change of tubulin at the tip of the growing MT, necessary for proper incorporation of new tubulin dimers into the MT lattice (see reviews [1,2])
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